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Inactivation of kindlin-3 increases human melanoma aggressiveness through the collagen-activated tyrosine kinase receptor DDR1

Oncogene (2024)Cite this article

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Abstract

The role of the focal adhesion protein kindlin-3 as a tumor suppressor and its interaction mechanisms with extracellular matrix constitute a major field of investigation to better decipher tumor progression. Besides the well-described role of kindlin-3 in integrin activation, evidence regarding modulatory functions between melanoma cells and tumor microenvironment are lacking and data are needed to understand mechanisms driven by kindlin-3 inactivation. Here, we show that kindlin-3 inactivation through knockdown or somatic mutations increases BRAFV600mut melanoma cells oncogenic properties via collagen-related signaling by decreasing cell adhesion and enhancing proliferation and migration in vitro, and by promoting tumor growth in mice. Mechanistic analysis reveals that kindlin-3 interacts with the collagen-activated tyrosine kinase receptor DDR1 (Discoidin domain receptor 1) modulating its expression and its interaction with β1-integrin. Kindlin-3 knockdown or mutational inactivation disrupt DDR1/β1-integrin complex in vitro and in vivo and its loss improves the anti-proliferative effect of DDR1 inhibition. In agreement, kindlin-3 downregulation is associated with DDR1 over-expression in situ and linked to worse melanoma prognosis. Our study reveals a unique mechanism of action of kindlin-3 in the regulation of tumorigenesis mediated by the collagen-activated tyrosine kinase receptor DDR1 thus paving the way for innovative therapeutic targeting approaches in melanoma.

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Fig. 1: Lack of kindlin-3 expression promotes proliferation and migration of BRAFV600mut melanoma cells on collagen I.
Fig. 2: Kindlin-3 mutations promote melanoma cells malignant properties.
Fig. 3: Loss of kindlin-3 modulates DDR1 expression and inhibits cells adhesion on collagen I.
Fig. 4: Kindlin-3 interacts with DDR1 and modulates DDR1/β1-integrin complexes on collagen I.
Fig. 5: Lack of kindlin-3 improves in part DDR1-IN-1 inhibitor effect through DDR1/FAK pathway.
Fig. 6: Kindlin-3 expression in human melanomas is associated with pathological characteristics and better survival, and inversely correlates with DDR1 expression.
Fig. 7: Schematic involvment of kindlin-3 inactivation in melanoma cells aggressiveness.

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Data availability

The data generated in this study are available within the article and its supplementary data files. Additional data is available on request from corresponding author on reasonable request.

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Acknowledgements

We thank technological platform of the Institut Recherche Saint-Louis (IRSL) and Dr Véronique Parietti and the coworkers of the Animal Experimental Facilities. The authors thank the participation of the oncodermatologists of the Dermatology Department of Saint-Louis Hospital, Paris.

Funding

This study was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), the Université Paris Cité and the Société Française de Dermatologie (SFD). BL was supported by La Fondation de l’Avenir (Bourse Legs Cancérologie). This work was supported by funding from the integrated cancer research center “SiRIC InsiTu : Insights into cancer : From inflammation to tumor” (grant number INCa-DGOS-INSERM-ITMO Cancer_18008).

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Author notes

  1. These authors contributed equally: Coralie Reger De Moura, Baptiste Louveau.

Authors and Affiliations

  1. Department of Pharmacology and Tumor Genomics, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, F-75010, Paris, France

    Coralie Reger De Moura, Baptiste Louveau, Fanélie Jouenne, Paul Vilquin, Aurélie Sadoux, Suzanne Menashi & Samia Mourah

  2. Université Paris Cité, INSERM UMR-S 976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI), F-75010, Paris, France

    Coralie Reger De Moura, Baptiste Louveau, Fanélie Jouenne, Suzanne Menashi, Nicolas Dumaz, Céleste Lebbé & Samia Mourah

  3. Department of Pathology, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, F-75010, Paris, France

    Maxime Battistella & Yaelle Bellahsen-Harrar

  4. Department of Dermatology and CIC, Hôpital Saint Louis, Cancer Institute, Assistance Publique-Hôpitaux de Paris, F-75010, Paris, France

    Céleste Lebbé

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Contributions

CL and SM designed and supervised the study; CRdM and BL performed the experiments, analyzed, interpreted the data and wrote the manuscript; AS performed genomic and RNA-seq experiments; YB performed immunohistochemistry analyses; FJ, PV, MB and ND provided material resources; ND, CL, SM and SM revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Samia Mourah.

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Ethics approval and consent to participate

The study was conducted according to the guidelines of 2009 American Joint Committee on Cancer (AJCC). All patients signed written informed consent according to Helsinki guidelines and the study was approved by the INSERM institutional Review Board and Ethics Committee in Paris, France (IRB N°00006477). This study was approved by the Committee on the Ethics of Animal Experiments of the French Ministry of Agriculture (Permit N°B751008-22952).

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Reger De Moura, C., Louveau, B., Jouenne, F. et al. Inactivation of kindlin-3 increases human melanoma aggressiveness through the collagen-activated tyrosine kinase receptor DDR1. Oncogene (2024). https://doi.org/10.1038/s41388-024-03014-3

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